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Principal Investigator: Raiees Ahmad Andrabi
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2023
Award: $805,612
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus identified at the end of
2019, has led to the current global pandemic. The SARS-CoV-2 virus belongs to the subgenus sarbecovirus of
the genus betacoronavirus, the genus from which two SARS-CoV-2 closely related viruses (SARS-CoV-1 and
MERS-CoV) have crossed the species barrier to humans in the past 17 years. These coronaviruses have
crossed into humans through zoonotic transmissions from animal reservoirs highlighting a potential threat for
future spillovers. Therefore, development of intervention strategies that can mitigate outbreaks of future
coronaviruses is critical. To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines
capable of eliciting neutralizing antibody (nAb) responses against diverse CoVs. Currently there are two major
challenges to develop prophylactic vaccine-based strategies against coronaviruses; 1) identification of CoV spike
broadly neutralizing antibody (bnAb) sites for vaccine targeting; and 2) the development of vaccine strategies
that can reproducibly induce durable and protective bnAb responses against a broad range of coronaviruses. In
this R01 grant application, we will squarely address these knowledge gaps by employing a bnAb epitope based
rational vaccine design approach to develop immunogens and immunization strategies that can induce
coronavirus protective bnAb responses by vaccination. The project consists of 3 aims: Aim #1 will design novel
spike S2 stem bnAb site targeting vaccine immunogens using a rational reverse vaccine engineering approach.
Using CoV spike S2 stem helix bnAbs and their UCAs we will design, CoV S2 stem peptide-based nanoparticles,
rationally engineered S2 bnAb germline-targeting S-protein trimer immunogens and their multimerized
nanoparticle versions that can efficiently in vivo activate B cell precursors targeting the S2 stem region conserved
across β-CoV spikes. Aim #2 will iteratively evaluate and optimize prime boost immunization strategies in
appropriate pre-clinical animal models to develop vaccine protocols that can reproducibly induce durable and
protective bnAb responses against diverse β-CoVs. We will assess the in vivo protective efficacy of the vaccine-
induced bnAb responses in appropriate virus challenge models. Aim #3 will generate spike S2 stem helix bnAb
based “super antibodies” against β-coronaviruses by utilizing rational antibody engineering approaches. The
overall goal of this R01 grant proposal is to rationally design novel vaccine immunogen candidates, develop
robust vaccination strategies that can induce durable protective bnAb responses against a broad range of β-
coronaviruses and develop “super antibody” molecules promising for broad coronaviruses intervention strategies
to mitigate SARS-CoV-2 variants of concern and emerging coronaviruses as part of pandemic preparedness.
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Evolution><Elements><Engineering><Epitopes><Future><Gametes><Genetic><Germ Cells><Germ-Line Cells><Goals><Grant Proposals><HCoV><Health><Human><Immune response><Immunological response><In Vitro><Intervention><Intervention Strategies><Knowledge><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Methods><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular><Molecular Interaction><Peptides><Preventative vaccine><Preventive vaccine><Property><Prophylactic vaccine><Protein Engineering><Proteins><Reproducibility><Reproductive Cells><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated 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acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Sex Cell><Site><Testing><Translating><Transmission><Vaccination><Vaccine Design><Vaccines><Virus><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><activated B cells><antibody engineering><beta CoV><beta coronavirus><beta coronavirus vaccine><betaCoV><betacoronavirus><betacoronavirus vaccine><clinical test><corona virus><corona virus disease 2019><corona virus emergence><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus of pandemic concern><coronavirus of pandemic potential><coronavirus pandemic><coronavirus spike 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